Defending the end zone: studying the players involved in protecting chromosome ends

Abstract

The linear nature of eukaryotic chromosomes leaves natural DNA ends susceptible to triggering DNA damage responses. Telomeres are specialized nucleoprotein structures that comprise the "end zone" of chromosomes. Besides having specialized sequences and structures, there are six resident proteins at telomeres that play prominent roles in protecting chromosome ends. In this review, we discuss this team of proteins, termed shelterin, and how it is involved in regulating DNA damage signaling, repair and replication at telomeres.

Figure 1. Shelterin: defender of the end zone

Shelterin is composed of six players: TRF1, TRF2, TIN2, RAP1, TPP1 and POT1. TRF1 is a negative regulator of telomere length and is required to prevent replication fork stalling at telomeres. TRF2-RAP1 protects telomeres from engaging in an ATM-dependent DNA damage response (DDR), while TPP1-POT1 binds to the single-stranded overhang to protect telomeres from activating an ATR-dependent DDR. Inappropriate activation of repair pathways at telomeres results in chromosome fusions and genome instability. TPP1-POT1 also regulates telomerase access to telomeres to influence telomere length.